7-5997426-GAAAAAAA-GAAAAAAAA

Variant names:

• chr7-5997426-G-GA
• rs60794673
• NM_000535.7:c.706-4dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000535.7(PMS2):​c.706-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (656 hom., cov: 0)
  • Exomes 𝑓: 0.087 (93 hom.)
• Consequence: PMS2 NM_000535.7 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:17
• Conservation: PhyloP100: 0.187
• Publications: 10 publications found

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 7-5997426-G-GA is Benign according to our data. Variant chr7-5997426-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 198429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	NM_000535.7	MANE Select	c.706-4dupT		splice_region intron	N/A	NP_000526.2	P54278-1
	PMS2	NM_001406866.1		c.892-4dupT		splice_region intron	N/A	NP_001393795.1	A0A8V8TNX6
	PMS2	NM_001322014.2		c.706-4dupT		splice_region intron	N/A	NP_001308943.1	A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMS2	ENST00000265849.12	TSL:1 MANE Select	c.706-4_706-3insT		splice_region intron	N/A	ENSP00000265849.7	P54278-1
	PMS2	ENST00000382321.5	TSL:1	c.706-4_706-3insT		splice_region intron	N/A	ENSP00000371758.4	P54278-2
	PMS2	ENST00000406569.8	TSL:1	n.706-4_706-3insT		splice_region intron	N/A	ENSP00000514464.1	P54278-3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 13498 AN: 133126 Hom.: 655 Cov.: 0

Gnomad AFR AF: 0.105

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.0791

Gnomad MID AF: 0.0138

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.101

GnomAD2 exomes AF: 0.0693 AC: 10016 AN: 144514 AF XY: 0.0685

Gnomad AFR exome AF: 0.0783

Gnomad AMR exome AF: 0.0866

Gnomad ASJ exome AF: 0.0498

Gnomad EAS exome AF: 0.0270

Gnomad FIN exome AF: 0.0755

Gnomad NFE exome AF: 0.0766

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0866 AC: 82744 AN: 955546 Hom.: 93 Cov.: 0 AF XY: 0.0847 AC XY: 41428 AN XY: 489020

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0937 AC: 2053 AN: 21904

American (AMR) AF: 0.0864 AC: 2770 AN: 32068

Ashkenazi Jewish (ASJ) AF: 0.0454 AC: 943 AN: 20768

East Asian (EAS) AF: 0.0171 AC: 574 AN: 33658

South Asian (SAS) AF: 0.0496 AC: 3254 AN: 65578

European-Finnish (FIN) AF: 0.0762 AC: 3601 AN: 47242

Middle Eastern (MID) AF: 0.0281 AC: 129 AN: 4586

European-Non Finnish (NFE) AF: 0.0958 AC: 65847 AN: 687336

Other (OTH) AF: 0.0843 AC: 3573 AN: 42406

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.101 AC: 13510 AN: 133168 Hom.: 656 Cov.: 0 AF XY: 0.0988 AC XY: 6295 AN XY: 63732

African (AFR) AF: 0.105 AC: 3671 AN: 34958

American (AMR) AF: 0.114 AC: 1503 AN: 13140

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 143 AN: 3222

East Asian (EAS) AF: 0.0287 AC: 135 AN: 4710

South Asian (SAS) AF: 0.0386 AC: 163 AN: 4224

European-Finnish (FIN) AF: 0.0791 AC: 574 AN: 7254

Middle Eastern (MID) AF: 0.0113 AC: 3 AN: 266

European-Non Finnish (NFE) AF: 0.111 AC: 6929 AN: 62674

Other (OTH) AF: 0.104 AC: 194 AN: 1866

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	4	Lynch syndrome 4 (5)
-	-	5	not specified (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Lynch syndrome (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	1	-	Lynch syndrome 1 (1)
-	-	1	Mismatch repair cancer syndrome 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs60794673; hg19: chr7-6037057; COSMIC: COSV56220148; COSMIC: COSV56220148;